Altered cellular metabolism has been widely recognized as an emerging hallmark of cancer. Although recent advances in cancer metabolism research have begun to elucidate how metabolic changes support cancer cell growth and survival, alterations in fatty acid (FA) metabolism in cancer cells have received less attention. Increasing evidence has suggested that increased FA biosynthesis is needed not only to accommodate high rates of proliferation by providing building blocks for membrane synthesis, but also to enhance the ability of cancer cells to defend against oxidative stress- or chemotherapy-induced cell death by changing membrane lipid composition. Studies from our laboratories and others have demonstrated that FA synthase (FASN), a key enzyme of de novo lipid biosynthesis, is significantly upregulated in colorectal cancer (CRC). Our in vivo studies demonstrate that RNAi-mediated inhibition of FASN markedly reduces lung and hepatic CRC metastases and inhibits tumor angiogenesis. Collectively, our studies indicate FASN may serve as a potential target for novel therapeutic agents. Recently, several orally-available, reversible, potent and selective FASN small molecule inhibitors have been developed by our collaborator 3-V Biosciences. These agents have excellent pharmaceutical profiles and achieve antitumor effects at tolerated doses in a broad range of tumors including non-small cell lung cancer, ovarian and triple negative breast cancers. The translational goal of our project is to define the metabolic adaptations that occur in colon cancer and to conduct a clinical trial to evaluate the effect of FASN inhibitor, TVB-2640, on modulating cellular metabolism and proliferation in colon cancer patients. The central hypothesis for our proposal is that upregulation of FASN expression and activity occurs in a subset of colon cancer patients; therefore, these individuals would benefit from a therapeutic approach that includes targeted inhibition of de novo lipogenesis. The following Specific Aims are proposed: 1) to determine the effect of altered FASN expression on metabolic reprograming in colon cancer; 2) to delineate the anti-proliferative effect of FASN inhibition using patient-derived xenograft (PDX) models of colon cancer; and 3) to perform a pilot clinical trial in collaboration with 3-V Biosciences to assess pharmacodynamic effects on metabolic endpoints following short-term treatment with a novel FASN inhibitor (TVB-2640) prior to colon resection. Our highly collaborative group has the requisite expertise, innovative model systems, state-of-the-art technology and novel inhibitors to make rapid progress that will significantly advance our understanding of the FASN-mediated metabolic alterations of colon cancers and potentially provide novel treatment strategies based on a more focused and personalized approach.